Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

Hersh, David S.; Peng, Sen; Dancy, Jimena G.; Galisteo, Rebeca; Eschbacher, Jennifer; Castellani, Rudy J.; Heath, Jonathan; Legesse, Teklu; Kim, Anthony J.; Woodworth, Graeme F.; Tran, Nhan L.; Winkles, Jeffrey A.

doi:10.1007/s11060-018-2799-3

Cited by 9 publications

(10 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IDH1 Arg132His (R132H) mutation can affect the proliferation of glioma cells, which is slower than the corresponding wild-type IDH1 cells ( 8 , 9 ). Clinical studies ( 10 , 11 ) have shown that mutations in IDH1 were found to be associated with younger age, secondary GBMs (grade IV tumors that arise from biopsy-proven lower-grade predecessors), and increased overall survival (OS) ( 12 ). Further studies ( 13 , 14 ) have revealed that IDH1/2 mutations as good prognostic markers are universally present in grade II and III glioma and secondary glioblastoma, and serve an important role in the occurrence, development and evolution of glioma ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

IDH1 gene mutation activates Smad signaling molecules to regulate the expression levels of cell cycle and biological rhythm genes in human glioma U87‑MG cells

Gao

Zhang

et al. 2021

Mol Med Rep

View full text Add to dashboard Cite

Isocitrate dehydrogenase1 (IDH1) mutation is the most important genetic change in glioma. The most common IDH1 mutation results in the amino acid substitution of arginine 132 (Arg/R132), which is located at the active site of the enzyme. IDH1 Arg132His (R132H) mutation can reduce the proliferative rate of glioma cells. Numerous diseases follow circadian rhythms, and there is growing evidence that circadian disruption may be a risk factor for cancer in humans. Dysregulation of the circadian clock serves an important role in the development of malignant tumors, including glioma. Brain-Muscle Arnt-Like protein 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) are the main biological rhythm genes. The present study aimed to further study whether there is an association between IDH1 R132H mutation and biological rhythm in glioma, and whether this affects the occurrence of glioma. The Cancer Genome Atlas (TCGA) database was used to detect the expression levels of the biological rhythm genes BMAL1 and CLOCK in various types of tumor. Additionally, U87-MG cells were infected with wild-type and mutant IDH1 lentiviruses. Colony formation experiments were used to detect cell proliferation in each group, cell cycle distribution was detected by flow cytometry and western blotting was used to detect the expression levels of wild-type and mutant IDH1, cyclins, biological rhythm genes and Smad signaling pathway-associated genes in U87-MG cells. TCGA database results suggested that BMAL1 and CLOCK were abnormally expressed in glioma. Cells were successfully infected with wild-type and mutant IDH1 lentiviruses. Colony formation assay revealed decreased cell proliferation in the IDH1 R132H mutant group. The cell cycle distribution detected by flow cytometry indicated that IDH1 gene mutation increased the G 1 phase ratio and decreased the S phase ratio in U87-MG cells. The western blotting results demonstrated that IDH1 R132H mutation decreased the expression levels of the S phase-associated proteins Cyclin A and CDK2, and increased the expression levels of the G 1 phase-associated proteins Cyclin D3 and CDK4, but did not significantly change the expression levels of the G 2 /M phase-associated protein Cyclin B1. The expression levels of the positive and negative rhythm regulation genes BMAL1, CLOCK, period (PER s (PER1, 2 and 3) and cryptochrom (CRY)s (CRY1 and 2) were significantly decreased, those of the Smad signaling pathway-associated genes Smad2, Smad3 and Smad2-3 were decreased, and those of phosphorylated (p)-Smad2, p-Smad3 and Smad4 were increased. Therefore, the present results suggested that the IDH1 R132H mutation may alter the cell cycle and biological rhythm genes in U87-MG cells through the TGF-β/Smad signaling pathway.

show abstract

Section: Introductionmentioning

confidence: 99%

IDH1 gene mutation activates Smad signaling molecules to regulate the expression levels of cell cycle and biological rhythm genes in human glioma U87‑MG cells

Gao

Zhang

et al. 2021

Mol Med Rep

View full text Add to dashboard Cite

show abstract

“…In our analysis, TNFRSF12A was more highly expressed in IDH wild-type gliomas than gliomas with IDH mutations. One study reported that TNFRSF12A promoted the invasive phenotype of IDH1 wild-type gliomas, while IDH1-mutant gliomas exhibited low TNFRSF12A mRNA and protein levels compared with IDH1 wild-type gliomas (47).…”

Section: Discussionmentioning

confidence: 99%

A Novel Immune-Related Prognostic Biomarker and Target Associated With Malignant Progression of Glioma

et al. 2021

View full text Add to dashboard Cite

BackgroundGlioma is one of the most common malignancies in the central nervous system and has limited effective therapeutic options. Therefore, we sought to identify a suitable target for immunotherapy.Materials and MethodsWe screened prognostic genes for glioma in the CGGA database and GSE43378 dataset using survival analysis, receiver operating characteristic (ROC) curves, independent prognostic analysis, and clinical correlation analysis. The results were intersected with immune genes from the ImmPort database through Venn diagrams to obtain likely target genes. The target genes were validated as prognostically relevant immune genes for glioma using survival, ROC curve, independent prognostic, and clinical correlation analyses in samples from the CGGA database and GSE43378 dataset, respectively. We also constructed a nomogram using statistically significant glioma prognostic factors in the CGGA samples and verified their sensitivity and specificity with ROC curves. The functions, pathways, and co-expression-related genes for the glioma target genes were assessed using PPI networks, enrichment analysis, and correlation analysis. The correlation between target gene expression and immune cell infiltration in glioma and the relationship with the survival of glioma patients were investigated using the TIMER database. Finally, target gene expression in normal brain, low-grade glioma, and high-grade glioma tissues was detected using immunohistochemical staining.ResultsWe identified TNFRSF12A as the target gene. Satisfactory results from survival, ROC curve, independent prognosis, and clinical correlation analyses in the CGGA and GSE43378 samples verified that TNFRSF12A was significantly associated with the prognosis of glioma patients. A nomogram was constructed using glioma prognostic correlates, including TNFRSF12A expression, primary-recurrent-secondary (PRS) type, grade, age, chemotherapy, IDH mutation, and 1p19q co-deletion in CGGA samples with an AUC value of 0.860, which illustrated the accuracy of the prognosis prediction. The results of the TIMER analysis validated the significant correlation of TNFRSF12A with immune cell infiltration and glioma survival. The immunohistochemical staining results verified the progressive up-regulation of TNFRSF12A expression in normal brain, low-grade glioma, and high-grade glioma tissues.ConclusionWe concluded that TNFRSF12A was a viable prognostic biomarker and a potential immunotherapeutic target for glioma.

show abstract

“…PDGFB and SERPINE1 mRNA expression data corresponding to 10 normal brain and 548 GBM specimens were downloaded from the TCGA data portal (Level 3 data) (Cancer Genome Atlas Research Network, 2008) and analyzed as previously described (Hersh, Peng, et al, 2018).…”

Section: Methodsmentioning

confidence: 99%

Elevated fibroblast growth factor‐inducible 14 expression transforms proneural‐like gliomas into more aggressive and lethal brain cancer

Connolly

Galisteo

et al. 2021

Glia

Self Cite

View full text Add to dashboard Cite

High‐grade gliomas (HGGs) are aggressive, treatment‐resistant, and often fatal human brain cancers. The TNF‐like weak inducer of apoptosis (TWEAK)/fibroblast growth factor‐inducible 14 (Fn14) signaling axis is involved in tissue repair after injury and constitutive signaling has been implicated in the pathogenesis of numerous solid cancers. The Fn14 gene is expressed at low levels in the normal, uninjured brain but is highly expressed in primary isocitrate dehydrogenase wild‐type and recurrent HGGs. Fn14 signaling is implicated in numerous aspects of glioma biology including brain invasion and chemotherapy resistance, but whether Fn14 overexpression can directly promote tumor malignancy has not been reported. Here, we used the replication‐competent avian sarcoma‐leukosis virus/tumor virus A system to examine the impact of Fn14 expression on glioma development and pathobiology. We found that the sole addition of Fn14 to an established oncogenic cocktail previously shown to generate proneural‐like gliomas led to the development of highly invasive and lethal brain cancer with striking biological features including extensive pseudopalisading necrosis, constitutive canonical and noncanonical NF‐κB pathway signaling, and high plasminogen activator inhibitor‐1 (PAI‐1) expression. Analyses of HGG patient datasets revealed that high human PAI‐1 gene (SERPINE1) expression correlates with shorter patient survival, and that the SERPINE1 and Fn14 (TNFRSF12A) genes are frequently co‐expressed in bulk tumor tissues, in tumor subregions, and in malignant cells residing in the tumor microenvironment. These findings provide new insights into the potential importance of Fn14 in human HGG pathobiology and designate both the NF‐κB signaling node and PAI‐1 as potential targets for therapeutic intervention. Main Points This work demonstrates that elevated levels of the TWEAK receptor Fn14 in tumor‐initiating, neural progenitor cells leads to the transformation of proneural‐like gliomas into more aggressive and lethal tumors that exhibit constitutive NF‐κB pathway activation and plasminogen activator inhibitor‐1 overexpression.

show abstract

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

Cited by 9 publications

References 48 publications

IDH1 gene mutation activates Smad signaling molecules to regulate the expression levels of cell cycle and biological rhythm genes in human glioma U87‑MG cells

IDH1 gene mutation activates Smad signaling molecules to regulate the expression levels of cell cycle and biological rhythm genes in human glioma U87‑MG cells

A Novel Immune-Related Prognostic Biomarker and Target Associated With Malignant Progression of Glioma

Elevated fibroblast growth factor‐inducible 14 expression transforms proneural‐like gliomas into more aggressive and lethal brain cancer

Contact Info

Product

Resources

About